A novel insight into the role of macrophage accessory cells in B cell activation was provided by the observation that the immune response to the thymic independent (T-I) antigen, TNP-Ficoll, was dependent upon the presence and function of splenic adherent accessory cells. The functional spleen adherent cell was identified as a phagocytic macrophage-like cell which bears the I-A gene product. The accessory cell for this T-I TNP-Ficoll response functioned to present antigen to B cells. This identifiable macrophage-B cell interaction was found to be obligately restricted to the Lyb 5+ B cell subset which appears late in normal B cell ontogenetic development and which is absent in hybrid mice which have received the X-linked immune deficiency gene of the CBA/N mouse. The existence of this important cell interaction required for activation of B cells in response to accessory cell dependent antigens such as TNP-Ficoll (T-I) and the thymic dependent (T-D) TNP-KLH provides explanation for the immune response deficit to the T-I and T-D antigens in mice which bear the X-linked CBA/N genetic defect.